ABSTRACT: Project 1 If an HIV-1-free generation is to be achieved, mother-to-child HIV-1 transmission (MTCT) of HIV-1 must be eradicated. While antiretroviral prophylaxis strategies effectively prevent MTCT, they do not eliminate transmission in high-risk settings such as acute maternal infection, development of maternal drug-resistant variants, and lack of antiretroviral drug access or adherence. An attractive solution is the development of immunologic interventions for MTCT, such as vaccines. Project 1 will focus on developing a maternal vaccination strategy to passively immunize the infant via placental transfer of IgG and mucosal delivery of breast milk antibody. The development of a maternal vaccine is supported by our recent findings, which show that reduced risk of MTCT can be predicted by high magnitude maternal antibody responses against the HIV-1 Envelope (Env) variable loop 3 (V3) and neutralization of tier 1 heterologous viruses. In addition, we showed that vaccination of pregnant and infant rhesus monkeys against Simian Immunodeficiency Virus (SIV) can partially protect against infant oral SIV acquisition. Finally, we demonstrated that HIV-1 Env MVA prime/protein boost immunization of lactating monkeys elicits both robust Env-specific IgA and neutralizing antibody responses in maternal breast milk. Importantly, these findings suggest that maternal vaccination to enhance easy-to-elicit Env-specific antibody responses could protect against oral HIV-1 acquisition via breastfeeding in early infancy, a time point when infant vaccination cannot offer protection. Thus, we hypothesize that maternal vaccination with an Env prime/boost strategy optimized to elicit robust, potentially- protective Env-specific maternal antibody responses will effectively reduce oral simian/human immunodeficiency virus (SHIV) acquisition in neonatal infant monkeys. In the first Aim of this proposal, we will compare the specificity and function of previously-identified breast milk-derived HIV-1 Env-specific IgG and IgA antibodies elicited by maternal MVA prime/Env T/F 1086.C boost immunization to define the potential benefits of breast milk antibody response induction. In Aim 2, we will determine whether maternal placentally transferred or breast milk-derived vaccine-elicited antibodies confer protection against acute oral SHIV challenge in infants, simulating acute maternal infection during lactation. Finally, in Aim 3, we will determine whether this maternal Env immunization strategy can enhance potentially protective maternal antibody responses in SHIV-infected, antiretroviral-treated pregnant monkeys and define their ability to reduce oral autologous SHIV acquisition in the SHIV-exposed infant. This preclinical study of the immunogenicity and effectiveness of maternal HIV-1 Env immunization for reduction of infant virus acquisition will define the feasibility of maternal HIV-1 immunization for elimination of pediatric HIV-1 infections.